Under normal circumstances, functional stimulation results in a regional increase in cerebral blood flow (CBF) termed "activation-flow coupling" (AFC). While it is often assumed that a regional CBF increase is required to supply oxygen and nutrients, studies of brain energy metabolism in response to functional activation have demonstrated that regional CBF increases in excess of metabolism, and more recent data confirm that cerebral blood flow changes are not regulated by either glycolytic or oxidative demands. Additionally, blood flow effects can be pharmacologically decoupled from brain activation without loss of at least electrophysiological responses. Studies from our laboratory have demonstrated that the AFC response is preserved over a broad range of baseline flow values caused by a variety of pathophysiological conditions including mild and severe ischemia and pharmacological modulation of CBF with theophylline, acetazolamide, and CO2. This data suggest that AFC may be mediated by an independent mechanism than that which regulates baseline CBF. We will examine AFC during graded ischemia, and hypothesize that the AFC response is dependent on residual neural activity and is correlated with the somatosensory evoked potential. Preliminary data demonstrate a neuroprotective effect of functional forepaw stimulation contralateral but not ipsilateral to the ischemic hemisphere in the rat filament model of MCA stroke. We propose a series of studies to examine the effects of functional stimulation on CBF, oxygen metabolism, and ischemic injury in acute MCA stroke to better characterize the effects of functional stimulation on cerebrovascular pathophysiology, brain injury, and neurological outcome in rats. It is hypothesized that functional forepaw stimulation improves outcome from focal forebrain ischemia because the AFC response produces an incremental CBF increase through collateral flow sources that exceeds the metabolic demands of stimulation. Changes in CBF and blood oxygenation will be monitored optically, and changes in oxygen metabolism will be calculated from these parameters. PUBLIC HEALTH RELEVANCE: Despite many years of research, there are no proven treatments for stroke. This project will characterize and extend exciting preliminary data in the rat showing that functional stimulation during the period of ischemia reduces the subsequent damage to the brain. The use of functional stimulation as treatment for stroke has obvious translational potential.